Long-term trends in cancer incidence and mortality among U.S. children and adolescents: a SEER database analysis from 1975 to 2018

Background Childhood and adolescent cancer represent a significant health burden in the United States. Current and precise epidemiological data are crucial to develop effective cancer control plans and ultimately reduce the burden of childhood and adolescent cancer. Methods We analyzed data obtained from cancer registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Age-standardized incidence and death rates, assessed using joinpoint analysis, were quantified as annual percentage changes (APC) and average percentage changes (AAPC). Results The overall cancer incidence rate in 2008–2018 was 187.9 per 1,000,000 persons. Cancer incidence rates demonstrated a sustained upward trend, with an APC of 0.8 from 1975 to 2018. Incidence rates during 2008–2018 remained stable among non-Hispanic Black children but increased among other racial and ethnic groups. Leukemias, central nervous system tumors, and lymphomas were the most common cancer groups for patients aged 0–19 years. Cancer death rates decreased among children [AAPC, −1.3 (95% CI, −1.5 to −1.1)] during 2009–2019, while were stable among adolescents during that period. Conclusions In this study, we analyzed cancer incidence and mortality rates and trends in children aged 0–19 years in the United States. Our findings revealed an overall increase in cancer incidence rates among children and adolescents, accompanied by a decline in cancer mortality rates over time. These rates and trends varied by age, sex, and particularly race and ethnicity, highlighting the significance of comprehending and addressing disparities and ultimately reducing the disease burden of childhood and adolescent cancer.


Introduction
Cancer is a formidable health challenge that affects individuals of all ages, even in children (ages 0-14 years) and adolescents (ages 15-19 years) (1).Childhood cancer encompasses a broad range of malignancies that can arise in various organs and tissues, which differ from the cancers found in adults (2).While childhood and adolescent cancer is relatively rare compared to cancer in adults, it remains a significant concern due to its profound impact on the lives of young patients and their families.
In the United States, childhood and adolescent cancer represents a significant health burden.Cancer is the leading disease-related cause of death in this age group (3).In 2023, it was estimated that 9,910 children and 5,280 adolescents received a diagnosis of cancer, while approximately 1,040 children and adolescents were expected to have died from the disease (4).On the other hand, when considering the disability burden caused by childhood and adolescent cancer, a study used disability-adjusted life-years (DALYs) as a metric and reported that childhood and adolescent cancer resulted in a substantial DALY burden, highlighting the long-term impact of the disease on quality of life and overall well-being (5).
Understanding accurate epidemiological data in this vulnerable population is crucial for health policy prioritization, developing cancer control plans, and ultimately reducing the burden of cancer-related morbidity and mortality (2).Previous studies have endeavored to determine the epidemiological characteristics in children and adolescents in the United States.Several of these studies described that at a specific time or evaluated the trends for limited periods (6)(7)(8), while others focused on specific cancer types (9)(10)(11).Research investigating the long-term trends in incidence and mortality rates by age, sex, and race and ethnicity among children and adolescents is lacking.Hence, this study aimed to expand on these studies to describe cancer incidence and mortality rates and trends in a more detailed way.By using data obtained from cancer registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, we evaluated the long-term trends and cross-sectional incidence and mortality rates for children and adolescent cancer.

Data source
Population-based cancer incidence and mortality data were obtained from cancer registries in the SEER Program.The SEER program was established in 1973 (SEER 9 registry) and has undergone 2 major expansions (SEER 13 in 1992 and SEER 18 in 2000) to incorporate additional areas.SEER 18 covers about 28% of the U.S. population.Hence, in order to enhance the representativeness of this study, the SEER 9 database was used to cover data from 1975 to 1991, the SEER 13 database to cover data from 1992 to 1999, and the SEER 18 database to cover data from 2000 to 2018.

Case definition
For the analysis of cancer incidence rates and trends, the study included patients aged 0-19 years diagnosed with a primary malignant neoplasm in the United States between 1975 and 2018.This age group encompassed children (aged 0-14 years) and adolescents (aged 15-19 years).For the analysis of cancer mortality rates and trends, the study included all individuals within this age population who died of malignant cancers between 1975 and 2019.Cancer diagnoses were categorized based on histology and primary site, according to the third edition of the International Classification of Childhood Cancer (ICCC-3).Cause of death was coded according to the International Classification of Diseases (ICD) categories, specifically ICD-8 to ICD-10 in this study.Rates and trends were presented by age, sex, and race and ethnicity.Race and ethnicity were divided into the following 5 mutually exclusive racial/ethnic groups: non-Hispanic White, non-Hispanic Black, non-Hispanic American Indian or Alaska Native (AI/AN), non-Hispanic Asian or Pacific Islander (API), and Hispanic (all races).Notably, given that rates categorized by expanded race (white, black, AI/AN, and API) and Hispanic ethnicity have been available since 1992, trends by racial and ethnic group have been calculated since 1992.Mortality rates and trends by ICD group were not displayed for non-Hispanic AI/AN and non-Hispanic API due to a small number of cases.

Statistical analysis
We used SEER*Stat software (version 8.4.1, developed by the National Cancer Institute and Information Management Services) to calculate the incidence and mortality rates (12).Rates were expressed per 1,000,000 persons and were age-adjusted to the 2000 US standard population (19 age groups, Census P25-1,130).Cross-sectional rates were calculated for incidence from 2008 to 2018 and for mortality from 2009 to 2019.Rates were considered unreliable and therefore not reported if there were fewer than 16 cases or deaths during the specified time period.Death rates were restricted to the top 12 causes of cancer death.Temporal trends in incidence  and death (1975-2019) rates were quantified by using annual percent change (APC) and average APC (AAPC), which is a summary representation of the trend over a specific time interval.The corresponding 95% confidence intervals (95% CI) were calculated using the parametric method in Joinpoint Regression Program, version 4.9.1.0.Trends were deemed unreliable and not calculated if there were fewer than 10 cases or deaths in any 1 calendar year (13).Statistical significance was determined using a t-test for the APC.For AAPC, a t-test was used when it lay within the last segment; otherwise, a z-test was used.Two-sided P < .05 was considered statistically significant.

Cancer incidence by age, sex, and race
The annual age-adjusted cancer incidence rate in patients aged 0-19 years was 129.6 (per 1,000,000 persons) in 1975 and increased to 191.2 by 2018.The overall cancer incidence rate in 2008-2018 was 187.9 and was higher in males (196.2) than in females (179.2).Cancer incidence rates over time showed an increasing long-term trend, with an APC of 0.8 during 1975-2018.Among boys, rates also increased with an APC of 0.  1A; Supplementary Table S1).
Table 1 presented the overall cancer incidence rates and trends in 2008-2018 for ICCC-3 cancer type by race and ethnicity.Rates by ICCC-3 group were not calculated for non-Hispanic AI/AN population because of few cases.Rates for females in every racial/ ethnic group all increased, and the greatest increase was observed in non-Hispanic API population with an AAPC of 2.3 (95% CI, 1.3-3.2);rates for males increased in almost all racial/ethnic groups except for non-Hispanic AI/AN, which was stable during that period.The highest total incidence rate for leukemias was in Hispanic population (61.1).Rates for leukemias increased among all racial/ethnic groups (non-Hispanic White, non-Hispanic Black, non-Hispanic API, and Hispanic), with the largest increase of rates for acute myeloid leukemia (AML) in non-Hispanic Black population [AAPC, 1.4 (95% CI, 0.1-2.7)].The highest rate for total lymphomas was in non-Hispanic White population (33.1).Rates for total lymphomas increased among all racial/        .95 (Continued) .09 VIa Nephroblastoma and other nonepithelial renal tumors

Cancer death rates and trends
Cancer death rates in patients aged 0-19 years decreased significantly over time from 51.5 in 1975 to 20.8 in 2019.Death rates decreased from 57.7 to 22.6 for males and from 44.9 to 18.9 for females during that period (Figure 3A).The overall cancer death rates have been decreasing since 1975 for both males and females.Table 2 showed the long-term trends and AAPC in 2009-2019 in death rates by age, sex, racial/ethnic group, and the top 12 common causes of death for patients aged 0-19 years.Between 1975 and 1996, the overall rates sharply decreased by 2.7% per year.From 2009 to 2019, rates decreased with an AAPC of 1.4.
As noted in previous findings, the incidence rates of pediatric thyroid cancer have been increasing since the 1970s (29).The increasing trends persisted across all racial and ethnic groups, with the highest rate found in non-Hispanic White and the lowest rate in non-Hispanic Black children.A study demonstrated that a sharp increase in incidence rate occurred after 2006, which could be partly attributed to the guidelines published by the American Thyroid Association in 2006 potentially leading to enhanced detection through improved diagnostic ultrasonography and ultrasonography-guided biopsies (10).In combination with the overdiagnosis, the actual increase in childhood thyroid cancer incidence rate, which might be associated with environmental exposures, in particular, exposure to ionizing radiation, could together contribute to the increasing trends in incidence of pediatric thyroid cancer (10,(30)(31)(32).
There were several limitations to this study.The SEER database, while comprehensive within the United States, is regionally selective and may not fully represent all geographic or demographic groups within the country.This might affect the extrapolation of our findings to states or areas not covered by the SEER program.Further studies might be necessary to confirm these trends in states or regions not represented in the SEER data.In addition, using metrics like cancer incidence and mortality rates could not thoroughly estimate the disease burden of childhood cancer given that the long-term effects of cancer treatments characterized by survivorship morbidity were overlooked (3).In addition, there is a lack of data pertaining to minor racial and ethnic groups, which may result in underestimates of cancer in these subpopulations.Finally, the joinpoint regression analysis used in our study, although powerful for identifying changes in trends, has limitations.The method assumes that changes in trends are best described by piecewise linear segments, which may not capture more complex patterns in the data.Moreover, the selection of too many or too few joinpoints can lead to overfitting or underfitting the model to the data, respectively.
In summary, we examined the cancer incidence and mortality rates and trends in children aged 0-19 years in the United States.Our findings demonstrated that the overall cancer incidence rates increased among children and adolescents, while the cancer mortality rates declined overall and for many cancer types over time.Rates and trends varied by age, sex, and especially race and ethnicity, underscoring the importance of understanding and addressing disparities and finally reducing the disease burden of childhood and adolescent cancer.

FIGURE 2
FIGURE 2 Cancer incidence rates of children, adolescents, and children and adolescents in the United States, 2008-2018, by the international classification of childhood cancer, third edition (ICCC-3) group.Rates were per 1000000 persons, age-standardized to the 2000 US standard population (19 age groups, Census P25-1,130).The ICCC-3 is displayed by abbreviated title.
the average annual percent change and is a weighted average of the APCs over the fixed interval 2008-2018 using the underlying Joinpoint model for the period of 1992-2018.AAPC was not calculated if case count was <10 cases in any 1 calendar year.
the average annual percent change and is a weighted average of the APCs over the fixed interval 2009-2019 using the underlying Joinpoint model for the period of 1975-2019.bIncidencetrends by races/ethnicities were calculated between 1992 and 2019.APC, annual percent change; CI, confidence interval; AAPC, average annual percent change.APC was not calculated if case count was <10 cases in any 1 calendar year.

TABLE 2
Joinpoint death rate trends for the ICD cancer group in children and adolescents (ages 0-19 years), United States, 1975-2019.
Supplementary TableS2presented the death rates and trends in 2009-2019 by cause of death for non-Hispanic White, non-Hispanic Black, and Hispanic populations.Notably, some of the rates and trends results could not be calculated due to the limited number of cases.During 2009-2019, among non-Hispanic White persons, death rates decreased for most of the common cancers except for bones and joints, soft tissue including heart, and miscellaneous malignant cancer, death rates for which remained stable during that period.Trends in

TABLE 2 Continued
rates for brain and other nervous system, bones and joints, and soft tissue including heart were stable among non-Hispanic Black persons.Trends in death rates for brain and other nervous system, bones and joints, soft tissue including heart, miscellaneous malignant cancer were table among Hispanic population. death